Itch accompanies many neurological, dermatological and systemic diseases and leads to suffering and loss in the quality of life. The peripheral neuronal mechanisms underlying this sensation in human are still poorly understood. The overall goal of our proposal is to determine how acute itch and the prolonged itch from a pruritic disease are encoded in the discharges of cutaneous nociceptors. We propose electrophysiological experiments in non-human primate to characterize the responses to pruritic chemical stimuli in subtypes of peripheral nociceptive nerve fibers and complementary, correlative psychophysical studies in human to determine the role of these different neuronal populations in itch sensation. We will test different models of itch coding, modulate neuronal activity in nociceptive afferents, and investigate the effect of such modulation on itch sensation. We will investigate how a single class of nociceptors can signal both strong chemical pain from capsaicin and itch from histamine, and define, for the first time, the discharge associated with allodynia vs. alloknesis and other dysesthesias. In a clinically relevant model of prolonged itch, namely the SADBE model of allergic contact dermatitis, we will investigate the neuronal mechanisms of spontaneous and enhanced itch to chemical stimuli using psychophysical studies in humans and electrophysiological recordings from nociceptive afferents in non-human primates. By studying both acute and prolonged itch, we will be able to identify, for the first tim, changes that occur in the nervous system in a clinically relevant itch condition. A better understanding of how nociceptors mediate the sensation of itch in normal and pruritic skin will increase the possibility of developing and evaluating novel, peripherally acting drugs that reduce the abnormal nociceptor function underlying chronic itch. RELEVANCE: Although itch is a significant clinical problem affecting millions of people worldwide, the neuronal mechanisms of this sensation in human are not well understood. Using a combination of psychophysical studies in human and electrophysiological studies in non-human primate, we will investigate how itch is encoded in the neuronal activity of different types of peripheral nerve fibers in normal skin and in inflamed and itchy skin produced by allergic contact dermatitis. The outcomes will lead to a better understanding of how acute itch in normal skin and prolonged itch from a clinically relevant pruritic disorder are encoded by nerve fibers and thereby provide potential neuronal targets for future development of peripherally acting anti-pruritic drugs.